Catalytic promiscuity is the ability of the active site of one enzyme to catalyze several chemical transformations. Understanding and controlling catalytic promiscuity are key to understanding the evolution of new enzymatic activity and to design new enzyme-catalyzed reactions for synthesis. The rationale presented here, which was used to increase the perhydrolase activity in an esterase or a lipase, may be used to design other enzymes with altered nucleophile selectivity and to catalyze stereoselective oxidations.